Since hominization the human genome has been under selective pressure to develop resistance against infectious diseases. For example, it is thought that malaria infection has been an important evolutionary force in the selection of various hemoglobinopathies and other red blood cell disorders (thalassemia, glucose-6-phosphate dehydrogenase deficiency, sickle cell trait, and hemoglobin C etc.) and their observed overlapping geographic distributions support this hypothesis. Similarly, the frequency of human apolipoprotein E (apo E: protein component of triglyceride-rich lipoprotein) epsilon 4 allele is extremely high in the malaria endemic areas of sub-Saharan Africa and in Papua New Guinea, suggesting that apo E phenotype E4/4 protects against malaria infection. An in vitro growth inhibition assay was used to test the hypothesis and provided evidence for an association between apo E4/4 and impaired infection of red blood cells by the human malarial parasite Plasmodium falciparum. Apo E4 allele of the spo E gene has been linked to the pathogenesis of Alzheimer's disease, cardiovascular disease and atherosclerosis, but the studies proposed herein are the first to investigate the role of human apo E4/4 in protecting against malaria infection. A preliminary ultrastructural study of P. falciparum blood stage parasites exposed to human plasma containing native Apo E4/4 has revealed that this molecule disrupts parasite cell membranes. It is not known if apo E4/4 produces these cytopathic effects merely by making contact with the parasite plasma membrane or whether it needs to be internalized in order to act. Consequently, a major aim of this proposal is to determine the precise site of interaction between apo E4/4 and the parasite by immunocytochemistry. Further to this, the study will be extended to at least 8 other lines of P. falciparum parasites originating from a variety of geographical locations in order to better characterize the role of apo E4 during malaria infection and will ultimately be repeated using highly purified apo E4/4, rather than plasma. These studies represent a unique approach in the battle against malaria and could provide the basis for the design of an entirely new class of anti-malarial drugs.